Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms

骨髓增生性肿瘤中异常的巨核细胞生成

基本信息

批准号：
8707548
负责人：
John D Crispino
金额：
$ 41.73万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707548
关键词：
Abnormal megakaryocyte Acute Megakaryocytic Leukemias Acute leukemia Affect Animal Model Apoptosis Biological Assay Bone Marrow CD34 gene CEBPA gene Cell Differentiation process Cell Line Cell surface Cells Clinical Trials Collaborations Commit Data Defect Development Differentiation Inducer Disease Effectiveness Employee Strikes GFI1B gene Genes Genetic Transcription Genetic Variation Growth Hematopoietic Hemorrhagic Thrombocythemia Human Institutes JAK2 gene LMO2 gene Large Megakaryocyte Lead Malignant - descriptor Megakaryocytes Megakaryocytopoieses Molecular Mus Mutation Myelofibrosis Myelogenous Myeloproliferative disease Nature Pathway interactions Patients Phenocopy Phenotype Plant Roots Platelet Count measurement Polycythemia Vera Polyploidy Primary Myelofibrosis Proliferating Regulation Research Sampling Severity of illness Signaling Molecule Specimen Symptoms Thrombocytopenia Thrombopoiesis Transplantation Work aurora-A kinase epigenetic variation in vitro activity in vivo inhibitor/antagonist innovation leukemia mutant novel novel strategies progenitor programs public health relevance small molecule thrombocytosis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Aberrant regulation of megakaryocyte development is a feature of both essential thrombocythemia (ET) and primary myelofibrosis (PMF). Under normal conditions, committed megakaryocyte progenitors proliferate to a limited extent and then give rise to small numbers of differentiated and polyploid megakaryocytes. However, upon acquisition of mutations in key signaling molecules, such as MPL or JAK2, megakaryocyte progenitors expand and lead to thrombocytosis in ET or myelofibrosis in PMF. The specific molecular changes and mechanisms responsible for the extreme differences in the megakaryocyte phenotype of the two disorders are unknown. In this project, we will identify transcriptional pathways that are dysregulated in PMF megakaryocytes and characterize the causes of aberrant megakaryopoiesis as compared to ET megakaryocytes. We will also determine whether small molecule inducers of megakaryocyte differentiation and polyploidization are effective at restraining the proliferation of aberrant megakaryocytes in MPNs. Finally, we will study the mechanism by which these compounds lead to differentiation and polyploidization of abnormal megakaryocytes. Our overall hypothesis is that megakaryocytes in PMF are abnormal because they aberrantly express myeloid transcription factors and that this program can be reversed with small molecule inducers of megakaryocyte polyploidization and differentiation. This work is innovative in that we are the first to comprehensively describe the differences between PMF and normal megakaryocytes at the molecular level. Moreover, we are using innovative small molecules to advance our understanding of MPNs and to develop new targeted therapies. Our work is significant in that none of the JAK2 inhibitors in clinical trials ameliorate bone marrow myelofibrosis in patients: our research aimed at identifying the root cause of this debilitating condition will aid in development of new therapies.

描述（由申请人提供）：巨核细胞发育的异常调节是原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）的一个特征。在正常情况下，定型巨核细胞祖细胞增殖有限，然后产生少量分化的多倍体巨核细胞。然而，一旦关键信号分子（例如 MPL 或 JAK2）发生突变，巨核细胞祖细胞就会扩张并导致 ET 中的血小板增多或 PMF 中的骨髓纤维化。造成这两种疾病巨核细胞表型极端差异的具体分子变化和机制尚不清楚。在这个项目中，我们将鉴定 PMF 巨核细胞中失调的转录途径，并描述与 ET 巨核细胞相比异常巨核细胞生成的原因。我们还将确定巨核细胞分化和多倍化的小分子诱导剂是否能有效抑制 MPN 中异常巨核细胞的增殖。最后，我们将研究这些化合物导致异常巨核细胞分化和多倍化的机制。我们的总体假设是，PMF 中的巨核细胞是异常的，因为它们异常表达骨髓转录因子，并且可以用巨核细胞多倍化和分化的小分子诱导剂来逆转该程序。这项工作的创新之处在于我们首次在分子水平上全面描述PMF与正常巨核细胞的差异。此外，我们正在使用创新的小分子来增进我们对 MPN 的理解并开发新的靶向疗法。我们的工作意义重大，因为临床试验中的 JAK2 抑制剂均无法改善患者的骨髓纤维化：我们的研究旨在确定这种使人衰弱的病症的根本原因，这将有助于开发新疗法。